Disease relevance of Acly

• In summary, the hypocitraturia of chronic metabolic acidosis is associated with an increase in ATP citrate lyase activity and protein abundance, and is partly reversed by inhibition of this enzyme [1].
• Inhibition of highly purified rat liver fatty acid synthetase occurs when it is assayed in the presence of the ATP citrate lyase reaction components [2].
• Hypothyroidism increased the activities of fatty acid synthase and ATP citrate lyase in brown, but not in white, adipocytes [3].
• ATP citrate lyase (EC 4.3.1.8.) was shown to be a major phosphorylation protein of a fraction derived from Zajdela rat hepatoma by chromatography on heparin-Ultrogel, after the incubation with [gamma-32P]ATP or [gamma-32P]GTP [4].
• Administration of CT (synthetic [Asu107] eel CT; 80 MRC mU/100 g body weight) produced significant increases in ATP citrate lyase activity and calcium content in the hepatic cytosol of intact and thyroparathyroidectomized rats [5].

High impact information on Acly

• The evidence suggests that there is a calcium-dependent transfer of mitochondrial acetyl coenzyme A into the cholinergic synaptoplasm, which is apparently devoid of the citrate cleavage enzyme, and is there converted into acetylcholine [6].
• The present study addressed the effect of chronic metabolic acidosis on a cytosolic enzyme of citrate metabolism, ATP citrate lyase [1].
• Hypokalemia, which causes only intracellular acidosis, caused hypocitraturia and increased renal cortical ATP citrate lyase activity by 28% [1].
• Similarly, the activity of liver acetyl CoA carboxylase, fatty acid synthetase, citrate cleavage enzyme, malate dehydrogenase, and glucose-6-phosphate dehydrogenase was diminished in U [7].
• In addition, transient expression of a constitutively active protein kinase B in primary adipocytes mimicked the effect of insulin on ATP-citrate lyase phosphorylation [8].

Chemical compound and disease context of Acly

• Highly purified rat liver fatty acid synthetase is completely inhibited when assayed in the presence of a coenzyme A-depleting system such as that catalyzed by phosphotransacetylase, acetyl-CoA synthetase, or ATP citrate lyase [9].
• Diabetic rats in both diet groups were characterized by hypoinsulinemia, hyperglycemia (6.8-7.0 fold increase) and significant decreases (p < 0.001) in the activities of glycogen synthase, phosphorylase and lipogenic enzymes, ATP-citrate lyase, glucose 6-phosphate dehydrogenase and malic enzyme in liver [10].
• We examined whether dietary supplementation of hydroxycitrate (HCA), a competitive inhibitor of the extramitochondrial enzyme ATP-citrate-lyase, which inhibits lipogenesis, reduces food intake and body weight regain in rats after 10-15% weight loss [11].
• Thyroxine (25 micrograms/100 g body weight) treatment for 1 month increased the specific activity of isocitrate dehydrogenase (NADP+) but the specific activities of ATP-citrate lyase, malate dehydrogenase and malic enzyme were inhibited [12].

Biological context of Acly

• The isolation and characterization of the mRNA for ATP citrate-lyase will allow further studies on the reaction mechanism and metabolic regulation of this key enzyme in lipogenesis and cholesterogenesis [13].
• During rat development, the ATP citrate-lyase mRNA was relatively high in the liver at parturition, followed by a reduction in its level during suckling [13].
• We have isolated a full-length cDNA copy of 4.3 kilobase pairs encoding the ATP-citrate lyase mRNA by screening rat liver cDNA library using oligonucleotide probes designed from peptide sequences obtained from the purified rat enzyme [13].
• Six Sp1 binding sites and CAAT box exist in the region from transcription start site to -419 bp which showed the highest promoter activity in ACL promoter previously [14].
• Reverse transcription-polymerase chain reaction showed two forms of ACL mRNA; the one containing complete exons and the other lacking exon 14 were found in the brain, kidney, mammary gland, lung and liver [15].

Anatomical context of Acly

• The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes [8].
• We have identified 32P-labeled acetyl-CoA carboxylase and 32P-labeled ATP-citrate lyase by immunoprecipitation of a rat hepatocyte microsomal preparation [16].
• In the transition between the fasting state (low rates of lipogenesis) and fasting/re-feeding (high rates), the fraction of total cytosolic plus microsomal acetyl-CoA carboxylase in the microsomes increases from 6% to 43%, whereas the microsomal proportion of total fatty acid synthetase and ATP-citrate lyase remains approximately 10% [16].
• ATP-citrate lyase phosphorylation in rat adipose tissue [17].
• The level of phosphorylation of PC12 cell ATP-citrate lyase by phosphorylated NDPK was comparable with that by ATP [18].

Associations of Acly with chemical compounds

• The functional importance of cataplerosis via citrate for glucose-induced insulin release was further supported by the observation that two ATP-citrate lyase inhibitors, radicicol and (-)-hydroxycitrate, block part of glucose-stimulated release in beta-cells [19].
• ATP citrate-lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues [13].
• Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo substrate for protein kinase B [8].
• MALDI-TOF mass spectrometry revealed the protein to be ATP-citrate lyase, suggesting that the two phosphospecific antibodies recognize phosphoserine 454, a previously reported insulin- and isoproterenol-stimulated ATP-citrate lyase phosphorylation site [8].
• Chloramphenicol acetyltransferase assay of ACL promoter suggested that multiple Sp1 sites might be involved in the ACL transcription [14].

Physical interactions of Acly

• Influence of glucagon or 5-(tetradecyloxy)-2-furoic acid on binding to mitochondria and phosphorylation of ATP-citrate lyase [20].

Enzymatic interactions of Acly

• Furthermore, ATP-citrate lyase was phosphorylated in vitro by recombinant protein kinase B on the same site [8].
• Thus, the site on ATP-citrate lyase phosphorylated by the cAMP-dependent protein kinase in vitro resides on the same octapeptide as the site of glucagon-stimulated phosphorylation in intact hepatocytes [21].
• Native acetyl CoA carboxylase was phosphorylated by catalytic subunit of cyclic AMP-dependent protein kinase and ATP-citrate lyase kinase to 1 and 0.5 mol/subunit respectively [22].

Regulatory relationships of Acly

• Transforming growth factor beta (TGF-beta) activates ATP citrate lyase in freshly isolated rat liver hepatocytes in a time dependent manner [23].
• The role of the cyclic AMP-dependent protein kinase in the glucagon-stimulated phosphorylation of ATP-citrate lyase [24].

Other interactions of Acly

• These results suggest that Sp1 is one of the most important transcription factors for ACL promoter to produce basal and induced transcription by low fat/high carbohydrate diet [14].
• Tryptic digestion of 32P-labeled ATP-citrate lyase purified from 32P-labeled hepatocytes exposed to glucagon yielded a major 32P-labeled peptide of identical amino acid composition with that indicated above [21].
• Reactivity and inhibitor potential of hydroxycitrate isomers with citrate synthase, citrate lyase, and ATP citrate lyase [25].
• In contrast, adipose tissue fatty acid synthetase was increased by 50% and citrate cleavage enzyme and malic enzyme by 30% by 9 days of age [26].
• 9. The periportal/perivenous ratio of ATP citrate-lyase mass was 1.4, and fatty acid synthase exhibited the largest periportal/perivenous mass gradient, having a ratio of 3 [27].

Analytical, diagnostic and therapeutic context of Acly

• Expression of this cDNA in bacteria, followed by immunoblotting with antibody directed against the ATP citrate-lyase, further demonstrated the identity of this clone [13].
• Rat ATP citrate-lyase. Molecular cloning and sequence analysis of a full-length cDNA and mRNA abundance as a function of diet, organ, and age [13].
• In the present study, trypsin-digested, radiolabeled ATP-citrate lyase from rat epididymal fat pads was analyzed by high performance liquid chromatography [17].
• The ATP citrate lyase activity in desalted crude extracts and 11% polyethylene glycol-precipitated fractions is inhibited but the enzyme purified by dye affinity chromatography is unaffected [28].
• The periportal/perivenous gradients for acetyl-CoA carboxylase, ATP citrate-lyase and fatty acid synthase observed in fed (and fasted) males were abolished when animals were fasted (48 h) and refed (30 h) with a high-carbohydrate/low-fat diet [27].

References